tbuckley/cabot-search huggingface dataset:
Abstract 85: Senescent cells promote breast cancer tumorigenesis
Authors: Jiayu (Jennifer) Ye, Ana Paula Delgado, Qihao Ren, Robert S. Powers, Sheila A. Stewart
Journal: Cancer Research (2023)

Abstract Age is the largest risk factor for breast cancer development. While numerous changes arise with age, we posit that the accumulation of p16INKA4 (p16)+ senescent stromal cells—which express cytokines, chemokines, and enzymes together recognized as senescence-associated secretory phenotype (SASP)—promote cancer progression. Indeed, high p16 positivity in stroma strongly correlates with breast cancer recurrence. To investigate how senescent stroma impact tumorigenesis, we crossed MMTV-PyMT (PyMT) mice that spontaneously develop mammary tumors to INK-ATTAC (INK) mice, which allows selective elimination of p16+ cells. Depletion of p16+ stroma in PyMT/INK mice led to a significantly delayed tumor onset and changes in tumor-infiltrating immune cells, both of which could be recapitulated by treating PyMT mice with a senolytic drug. scRNA-seq analyses of murine and human tumor samples revealed that senescence is restricted to a specific cancer associated fibroblasts (CAF) subpopulation that expresses numerous immune and extracellular matrix SASP factors that could impact T cells and Natural Killer (NK) cells. We refer to these cells as senescent CAFs (senCAFs). To assess the impact of senCAFs on T and NK cells’ anti-tumor effect, we depleted each population and found that the elimination of senCAFs no longer restricted tumor development in the absence of NK cells. We thus focused on addressing how senCAFs modulate NK cell function. Together our data highlight how senescent CAFs contribute to mammary gland tumorigenesis by modifying tumor microenvironment. Citation Format: Jiayu (Jennifer) Ye, Ana Paula Delgado, Qihao Ren, Robert S. Powers, Sheila A. Stewart. Senescent cells promote breast cancer tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 85.
Abstract 3689: Uncovering the metabolic vulnerabilities in activated B cell diffuse large B cell lymphoma
Authors: Satishkumar Singh, Fouad Choueiry, Anuvrat Sircar, Narendranath Epperla, Jiangjiang Zhu, Lalit Sehgal
Journal: Cancer Research (2023)

Abstract DLBCL is the most common B cell malignancy in adults accounting for 30-40% of non-Hodgkin lymphoma. Only 60% of these cases are curable, with activated B cell DLBCL (ABC-DLBCL) having inferior outcomes than the germinal center (GCB) DLBCL. The use of ibrutinib to treat non-responsive/relapsed ABC-DLBCL cases has significantly improved the treatment of this disease. However, in more than 40% of ABC-DLBCL cases, the disease progresses or develops resistance to ibrutinib. Thus, there is an urgent unmet need to understand the molecular basis of resistance mechanisms and identify novel therapeutic regimens to treat IR DLBCL. Utilizing high throughput metabolomics, we identified cysteine-methionine metabolism and alanine, aspartate, and glutamate metabolism to be deregulated in IR cells. We further identified interleukin four induced 1 (IL4I1), an L-amino acid oxidase that partakes in cysteine and methionine metabolism by contributing to the methionine salvage pathway. The amino acid cysteine contributes to cancer metabolic remodeling by a), in its free form, in redox control, as a component of the antioxidant glutathione or its involvement in protein s-cysteinylation, b), as a substrate for the production of hydrogen sulfide (H2S), which feeds the mitochondrial electron transfer chain and mediates persulphidation of ATPase and glycolytic enzymes, thereby stimulating cellular bioenergetics; and, c), as a carbon source for epigenetic regulation, biomass production, and energy production. Consistent with this, we show that loss of IL4I1 expression induced aberrant cysteine and methionine metabolism accompanied by metabolic reprogramming to OXPHOS, which collectively enabled increased drug tolerance of DLBCL. This adaptive metabolic mechanism exhibited increased cysteine and cystathionine intracellular levels in IR-DLBCL lacking IL4I1 expression. As cysteine and glutathione are scavengers of free radicals (mainly reactive oxygen species (ROS)), they can nullify the effects of the majority of oxidative or alkylating drugs used in cancer therapy, affording a vital resistance mechanism and disruption of cysteine homeostasis appears to be promising strategy for induction of cancer cell death and provide therapeutic approaches to treat Ibrutinib-resistant-ABC- DLBCL for improved patient care. Citation Format: Satishkumar Singh, Fouad Choueiry, Anuvrat Sircar, Narendranath Epperla, Jiangjiang Zhu, Lalit Sehgal. Uncovering the metabolic vulnerabilities in activated B cell diffuse large B cell lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3689.
Abstract 1344: myCAFs and iCAFs have similar lineage
Authors: Thomas S. Walter, Lu Han, Michael Ostrowski
Journal: Cancer Research (2023)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stroma primarily composed of cancer associated fibroblasts (CAFs). These fibroblasts are a diverse population of cells; some groups of fibroblasts have been shown to play tumor supporting roles while others have been shown to be tumor suppressing. Two prolific and well-characterized CAF subtypes—myofibroblasts (myCAFs) and inflammatory CAFs (iCAFs)—could potentially have different regulatory effects on tumor growth. Understanding the tissue origin of these two groups of CAFs could assist in understanding the complex and heterogeneous roles they might play in PDAC development. Previous studies in our group showed that the splanchnic mesenchyme, a layer of mesenchyme adjacent to the fetal pancreatic epithelium, gives rise to the majority of the total CAF population. Here, I aim to test the hypothesis that both iCAFs and myCAFs originate from the splanchnic mesenchyme. myCAFs have been previously observed to be proximal to tumor cells and express αSMA at a higher level, while iCAFs have been observed to be distal to tumor cells and express αSMA at a lower level. Here, we used a genetically engineered mouse PDAC model carrying KrasG12D/+;p53Frt/+;Pdx1FlpO/+;Isl1cre/+;R26Tomato/+ alleles. In this model, epithelial specific FlpO expression leads to Kras activation and p53 deletion, causing tumorigenesis. Simultaneously, splanchnic specific Cre expression leads to permanent tomato expression in the splanchnic descendants. The pancreata of these mice were harvested, fixed, and mounted onto slides. Co-immunostaining with αSMA and tomato was then done. The stained slides were scanned, and the Inform software was used to segment and phenotype the cells. More than 95% of αSMA high cells were tomato positive, and more than 95% of αSMA low cells were also tomato positive. We thus conclude that both myCAFs and iCAFs originate from the splanchnic mesenchyme. Consistent with previous in vitro studies, this lineage tracing study suggests that different CAF subtypes are likely due to patterning influenced by different factors within the tumor microenvironment. Citation Format: Thomas S. Walter, Lu Han, Michael Ostrowski. myCAFs and iCAFs have similar lineage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1344.
Abstract 3671: Targeting SLC2A1 and SLC38A2-mediated metabolic shift in SMARCA4/A2-dual deficient cancer
Authors: Xianbing Zhu, Zheng Fu, Shary Chen, Dionzie Ong, Giulio Aceto, Rebecca Ho, Jutta Steinberger, Eunice Li, David Huntsman, William Foulkes, Sidong Huang, Yemin Wang
Journal: Cancer Research (2023)

Abstract SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodelling complexes. These two ATPases are frequently inactivated in cancers and cancer cells deficient in either of them have been shown to depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, concomitant loss of SMARCA4 and SMARCA2 occurs in a subset of cancers that are often associated with very poor patient outcomes. Here, we uncover that dual loss of SMARCA4/A2 represses the expression of SLC2A1, encoding the glucose transporter GLUT1, which results in reduced glucose uptake and glycolysis accompanied with increased dependency on oxidative phosphorylation (OXPHOS); adapting to this, these SMARCA4/A2-dual deficient cells rely on elevated SLC38A2, an amino acid transporter, to increase glutamine import for fueling OXPHOS. Consequently, SMARCA4/A2-dual deficient cells and tumours are highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Furthermore, supplementation of alanine, also imported by SLC38A2, restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-dual deficient cancer cells. At a clinically relevant dose, alanine supplementation synergizes with OXPHOS inhibition or conventional chemotherapy eliciting marked antitumor activities in SMARCA4/A2-dual deficient cancer cell lines and patient-derived xenografts. Our findings reveal multiple druggable vulnerabilities of SMARCA4/A2-dual loss exploiting a GLUT1/SLC38A2-mediated metabolic shift. Particularly, unlike dietary deprivation approaches, alanine supplementation can be readily applied to current regimens for better treatment of these aggressive cancers. * Authors contributed equally# Co-corresponding Citation Format: Xianbing Zhu, Zheng Fu, Shary Chen, Dionzie Ong, Giulio Aceto, Rebecca Ho, Jutta Steinberger, Eunice Li, David Huntsman, William Foulkes, Sidong Huang, Yemin Wang. Targeting SLC2A1 and SLC38A2-mediated metabolic shift in SMARCA4/A2-dual deficient cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3671.
Abstract 3680: Multiomics analysis of triple negative breast cancer identifies potential metabolic vulnerability for overcoming the resistance of neoadjuvant therapy
Authors: Zuen Ren, Kiran Kurmi, Robert Morris, Shakchhi Joshi, Eric Zaniewski, Johannes Kreuzer, Gabrielle Elena Gioia, Wilhelm Haas, Marcia C. Haigis, Leif W. Ellisen
Journal: Cancer Research (2023)

Abstract Triple-negative breast cancer (TNBC) is a heterogeneous disease that remains currently medically incurable. We comprehensively analyzed clinical, proteomic, and metabolomic data of a cohort of 12 highly selected primary TNBCs. Among them, 7 patients after neoadjuvant chemotherapy had residual disease and micro- or macro-metastases that were non-pathologically complete response (non-pCR); 5 patients had pathologically complete response (pCR). Interestingly, both proteomic and metabolic profiling results revealed dramatically different molecular signatures in non-pCR relative to pCR. Non-pCR were enriched in metabolites involving aspartic acid, fumarate, nicotinamide, and adenosine that are critical intermediates for nitrogen recycling and tricarboxylic acid (TCA) cycle, which are essential fuels for tumor biomass. Moreover, non-pCR were enriched in urea cycle, oxidative phosphorylation, glycolysis, sirtuin signaling, nucleotide De Novo biosynthesis, which are resistance-associated. Putative therapeutic targets were identified in non-pCR patients. Collectively, our multiomics analysis demonstrated the heterogeneity of TNBCs at multi-levels and enabled the development of personalized therapies targeting unique tumor metabolic profiles. Citation Format: Zuen Ren, Kiran Kurmi, Robert Morris, Shakchhi Joshi, Eric Zaniewski, Johannes Kreuzer, Gabrielle Elena Gioia, Wilhelm Haas, Marcia C. Haigis, Leif W. Ellisen. Multiomics analysis of triple negative breast cancer identifies potential metabolic vulnerability for overcoming the resistance of neoadjuvant therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3680.
Abstract 1423: Regulation of SKP2 expression by methyltransferase-independent function of EZH2 in tumor growth and progression
Authors: Tania Marlyn Colon, Wei Dai, Byeong Hyeok Choi
Journal: Cancer Research (2023)

Abstract Skp2, an F box protein and a substrate-binding component of the SCFSkp2 ubiquitin E3 ligase complex, promotes ubiquitination and degradation of cyclin-dependent kinase inhibitors (CKIs), including p21, p27, and p57. Aberrant Skp2 expression is associated with many human cancers. EZH2 (Enhancer of Zeste Homologue 2) is a core catalytic subunit of the polycomb repressive complex 2 (PRC2) that can regulate gene expression by mediating the methylation of lysine 27 of histone H3 (H3K27me3). Accumulating evidence shows that EZH2 could bind to transcription factors and activate gene expression independently of its methyltransferase activity, leading to the activation of oncogenic signaling pathways and promoting the proliferation of tumor cells. Although the methyltransferase-independent function of EZH2 is important in cell proliferation, its mechanism in cell cycle regulation is still unclear. In this study, we demonstrate that EZH2 positively regulates Skp2 gene expression. We show that suppression of EZH2 expression resulted in a significant decrease of Skp2 protein levels, while the EZH2 enzymatic inhibitors, EPZ6438, had no impact on protein levels of Skp2, which suggests that EZH2 regulates Skp2 expression independently of its methyltransferase activity. Consistently, EZH2 depletion reduced the mRNA levels of Skp2, while EPZ6438 inhibited EZH2 methyltransferase activity without affecting the mRNA levels of Skp2. Importantly, EZH2 expression is positively correlated with the expression of EMT (Epithelial-mesenchymal transition) regulators (YAP1/TAZ, ZEB1, and Snail) and immune checkpoint proteins (FGL1 and Siglec-15) in cervical and pancreatic cancer cells, but reversely correlated with the expression of CKIs (p21, p27, and p57). Taken together, our findings suggest a novel mechanism by which EZH2 regulates tumorigenesis through its methyltransferase-independent function by regulating Skp2 expression. Targeting the methyltransferase-independent function of EZH2 may have therapeutic efficacy for cancer patients. Citation Format: Tania Marlyn Colon, Wei Dai, Byeong Hyeok Choi. Regulation of SKP2 expression by methyltransferase-independent function of EZH2 in tumor growth and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1423.
Abstract 1280: Role of soluble mesothelin in peritoneal metastasis
Authors: Neel M. Panchwagh, Theressa Ewa, Leela Rani Avula, Sarah Joseph, Chin-Hsien Tai, Samantha Sevilla, Vishal Koparde, Xianyu Zhang, Christine Alewine
Journal: Cancer Research (2023)

Abstract The cell-surface glycoprotein mesothelin (MSLN) is overexpressed in pancreatic adenocarcinoma (PDAC) and is positively correlated with tumor aggressiveness. MSLN knock-out (KO) PDAC cells have delayed growth of peritoneal metastases in mice. Complementation with wild-type MSLN rescued the phenotype, although complementation with MSLN containing a Y318A point mutation to ablate interaction with MSLN binding partner MUC-16 could not. Mature MSLN is shed into the tumor microenvironment to generate soluble MSLN (sMSLN). We hypothesized that sMSLN would promote peritoneal metastasis. We engineered MSLN C-terminal truncation mutants (∆599-WT and ∆599-Y318A) that lack the membrane attachment site and exist only in soluble form. Parent and MSLN KO PDAC cells were transduced with the vector constructs. These cells were injected into athymic nude mice and peritoneal tumor growth was measured 6 weeks later. MSLN KO cells complemented with ∆599-WT MSLN exhibited poor peritoneal tumor growth, while ∆599-Y318A resulted in growth rescue. We considered that sMSLN might exert a dominant negative effect because it competes for MUC-16 binding with membrane-bound MSLN but cannot facilitate cell-to-cell interaction. Expression of ∆599-WT inhibited tumor growth in parent cells, while ∆599-Y318A failed to do so. The activity of ∆599-Y318A in KO cells remained unexplained. We hypothesized that levels of mircoRNA-198, a purported tumor suppressor regulated by MSLN, might be altered by ∆599 expression and correlate with phenotype rescue. However, no change in microRNA-198 expression was observed in ∆599-expressing cells. We are continuing to investigate the mechanism for a novel activity of sMSLN that is unrelated to MUC-16 binding. Citation Format: Neel M. Panchwagh, Theressa Ewa, Leela Rani Avula, Sarah Joseph, Chin-Hsien Tai, Samantha Sevilla, Vishal Koparde, Xianyu Zhang, Christine Alewine. Role of soluble mesothelin in peritoneal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1280.
Abstract 3674: The polyamine acetylation enzyme SAT1 drives mesenchymal features and therapeutic resistance in glioblastoma
Authors: Ayush B. Rana, Timothy M. Horton, Vijay S. Thakur, Scott M. Welford
Journal: Cancer Research (2023)

Abstract Background: Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in adults. Characterization of GBM heterogeneity has identified four molecular subtypes based on transcriptomic profile: classical, neural, proneural and mesenchymal. Tumors harboring the mesenchymal gene signature are considered the most aggressive, invasive, and multitherapy-resistant. We identify the polyamine acetylation enzyme, SAT1 (spermidine/spermine N1-acetyltransferase 1) as a component of the mesenchymal gene signature and mesenchymal-associated gene sets including (1) Hallmark EMT and (2) Hallmark TNFa signaling via NF-κB. Design/Methods: To validate the role of SAT1 in driving mesenchymal features in vivo, we utilized a genetically flexible, CRISPR-based model of GBM. Tumor bearing mice were generated through in utero electroporation, resulting in ablation of PTEN, P53 and NF1 in developing cortical cells. SAT1 knockout was achieved through cloning of additional guide RNA’s against SAT1 into the tumor initiating plasmid. Results: In our model, we found increased levels of both SAT1 and acetylated polyamines in tumors compared to normal brain. Ablation of SAT1 was insufficient to prolong overall survival in mice but rendered the otherwise treatment resistant tumors highly sensitive to chemoRT. Bulk RNA sequencing of murine tumors revealed that SAT1 knockout resulted in reduced expression of the mesenchymal gene signature as well as genes implicated in EMT and TNFa/NFKb signaling. Conclusions: Collectively, these results reveal that SAT1 not only identifies mesenchymal GBM but also drives expression of the mesenchymal gene signature and mesenchymal features including multi-therapy resistance. Citation Format: Ayush B. Rana, Timothy M. Horton, Vijay S. Thakur, Scott M. Welford. The polyamine acetylation enzyme SAT1 drives mesenchymal features and therapeutic resistance in glioblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3674.
Abstract 3660: Bone mechanics influence cancer stem cell formation in osteosarcoma
Authors: Zunaira Shoaib, Aleczandria S. Tiffany, Brendan Harley, Joseph Irudayaraj, Timothy M. Fan
Journal: Cancer Research (2023)

Abstract Osteosarcoma (OS) is the most common primary tumor of bone and is characterized by rapid bone remodeling accompanied by structural and mechanical heterogeneity across the tumor. Chemoresistance and recurrence of OS can be attributed to a subpopulation of OS cells known as cancer stem-like cells (OS-CSCs). It can be hypothesized that tumor niches possessing distinct structural and mechanical properties could be harboring different OS cell populations, and certain niches might be more conducive for OS-CSCs formation and maintenance. To evaluate the presence of OS-CSCs, mineralized collagen scaffolds mimicking heterogenous bone niches with distinct structural and mechanical properties were fabricated by changing collagen content and pore alignment and were cultured with the highly metastatic human OS cell line 143B. Scaffolds with 47% collagen by weight but different pore alignment were chosen for further analysis because they possessed different stiffness and topographical properties. Cytoskeletal changes, epigenetic changes, chemoresistance and chemoresistance-related pathways, and the levels of stemness genes were assessed in the 3D scaffold cultures. A consistent trend of OS-CSC phenotype was observed in the cell population grown in the softer bone niches (12 kPa) with aligned pores as compared to stiffer niche (31 kPa) with non-aligned pores. The cell population growing in softer, aligned scaffolds had a significantly higher expression of stemness genes (OCT4, NANOG, SOX2, ALDH1A1) and drug efflux gene ABCB1 and increased chemoresistance to doxorubicin and cisplatin. Epigenetic changes associated with cisplatin resistance in OS such as a decrease in methyl transferase EZH2 accompanied by the upregulation of LIF/Notch and PRKCA pathways was observed in cells grown in softer, aligned niches. Fluorescent imaging of actin organization showed rounder cells in the aligned niche indicative of the CSC phenotype, and stretched, elongated cells in the non-aligned niche indicative of a differentiated phenotype. Our study showed that the mechanical and structural properties of bone niches influence the formation of distinct OS cell populations. A softer niche with an aligned structure is more conducive for maintaining OS-CSCs. Citation Format: Zunaira Shoaib, Aleczandria S. Tiffany, Brendan Harley, Joseph Irudayaraj, Timothy M. Fan. Bone mechanics influence cancer stem cell formation in osteosarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3660.